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United States Patent (19) 11 Patent Number: 5,760,032 Kitajima Et Al

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United States Patent (19) 11 Patent Number: 5,760,032 Kitajima Et Al USOO576.0032A United States Patent (19) 11 Patent Number: 5,760,032 Kitajima et al. 45) Date of Patent: Jun. 2, 1998 54) THIENYLAZOLE COMPOUND AND OTHER PUBLICATIONS THENOTRAZOLODIAZEPINE CO UND T. Tahara et al. "Syntheses and Structure-Activity Relation 75) Inventors: Hiroshi Kitajima; Syuji Ehara; ships of 6-Aryl-4H-s-triazolo3.4-cithieno23-e 14-di Hideaki Sato, all of Fukuoka; Minoru azepines" Arzneimittel Forschung Drug Research, vol. 28. Moriwaki, Osaka; Kenichi Onishi, 1978. Fukuoka, all of Japan Waiser, et al. J. Med. Chem. (1991). 34(3), 1209-21. G.N. Woodruff et al., "Cholecyst Antagonists". Annu. Rev. 73) Assignee: Yoshitomi Pharmaceutical Industries, Pharmacol. Toxicol., vol. 31, pp. 469-501, 1991. Ltd., Osaka, Japan J. Martinez et al., "Synthesis and Biological Activity of New Peptide Segments of Gastrin Exhibiting Gastrin Antagonist 21 Appl. No.: 750,025 Property". J. Med. Chem. vol. 27. pp. 1597-1601, 1984. 1. B.E. Evans, "Methods for Drug Discovery: Development of 22 PCT Filed: Jun. 1, 1995 Potent, Selective. Orally Effective Cholecystokinin Antago 86 PCT No.: PCT/JP95/01071 nists". J. Med. Chem., vol. 31, pp. 2235-2246, 1988. S371 Date: Nov. 22, 1996 Primary Examiner Mukund J. Shah Assistant Examiner-Bruck Kifle S 102(e) Date: Nov. 22, 1996 Attorney; Agent, or Firn-Wenderoth. Lind & Ponack 87 PCT Pub. No.: WO95/32964 57 ABSTRACT CT Pub. Date: Dec. 7, 1995 Thienylazole compounds (I) and thienotriazolodiazepine 30 Foreign Application Priority Data compounds (II) of the formulas Jun. 1, 1994 (JP) Japan ...................................... 6-00889 (I) (51) Int. Cl. ..................... A61K 31/55; CO7D 491/00; C07D 513/00; CO7D 515/00 52 U.S. Cl. ................................ ... 514/220; 540/560 58) Field of Search .............................. 540/560; 514/220 56) References Cited U.S. PATENT DOCUMENTS 4,094.984 6/1978 Weber et al. ........................... 424/269 (II) 4,199.588 4/1980 Weber et al. ... 424/267 5,190,939 3/1993 Rault et al. ... ... 514/220 5,532,233 7/1996 Weber et al. ........................... 514,219 FOREIGN PATENT DOCUMENTS 0 254 245 1/1988 European Pat. Off.. N 1 O 446 133 Al 9/1991 European Pat. Off. 0 559 891 A1 9/1993 European Pat. Off.. (CH)-h-Y-2 O 661 284A1 7/1995 European Pat. Off.. R3 2 361 398 3/1978 France. 2405682 8/1974 Germany. wherein R' and R are hydrogen, halogen. C-C alkyl and 49-42669 4/1974 Japan. the like; -A=B- is -N=N- and the like; R and R' 49-61197 6/1974 Japan. are hydrogen, C-C alkyl and the like; Y is -NHCO E. S. " -NHCONH-, -NHCOO- and the like; Z' and Z are " apan . aryl, heteroaryland the like; Ar is halogen-substituted phe 50-5809850-89369 5/19757/1975 Japan. nyll and the like;la and m isis 0 or an integer off 1-5. 50-148385 11/1975 Japan. 55-105681 8/1980 Japan. The compounds of the present invention have CCKantago 55-105682 8/1980 Japan. nistic action and gastrin antagonistic action, particularly 57-45754 9/1982 Japan. potent antagonistic action against CCK-A receptor, and are 55-12434 4/1989 Japan. useful as agents for the prophylaxis and treatment of central 1-294676 11/1989 Japan. and peripheral nervous system diseases (e.g. anxiety, 3-2232902-281.81 10/19911/1990 Japan. schizophrenia, and the like) and digestive diseases (e.g., 5-155871 6/1993 Japan pancreatitis, gastric ulcer, enterelicosis, irritable bowel syn 599 960 6/1978 siteland drome, constipation, and the like). 602741 7/1978 Switzerland. 603660 8/1978 Switzerland. S Claims, No Drawings 5,760,032 1 2 THENYLAZOLE COMPOUND AND juice, promotion of insulin release, control of pepsinogen THENOTRAZOLODIAZEPINE COMPOUND secretion, gastric delay of emptying, stimulation of ileum movement, contraction of gallbladder, and the like. The TECHNICAL FIELD physiological activity of CCK via CCK-B receptor report edly includes suppression of feeling of hunger, control of The present invention relates to novel thienylazole com dopaminergic nerves, control of pain and pain relief with pounds and thienotriazolodiazepine compounds having morphine. acceleration of memory, and the like, and CCK-B cholecystokinin (hereinafter abbreviated as CCK) and gas receptor antagonist is useful for the treatment and prophy trin antagonistic activities, which are utilized in the medical laxis of gastric ulcer and enterelicosis, emesis. control of field. appetite, pain, anxiety, dementia, schizophrenia, and the O like. BACKGROUND ART Mainly in experimental studies of pancreatitis in recent There have been heretofore reported a 2-thienyltriazole years, the involvement of CCK in the onset, evolution and aggravation of pancreatitis has been reported. Pancreatitis is compound (Japanese Patent Examined Publication No. a symptom wherein pancreatic tissues are digested by the 12434/1980) showing action on the central nervous system, 15 such as anti-convulsion activity and sedative activity; a enzyme secreted by the pancreas itself (autodigestion), and thienotriazolodiazepine compound (Japanese Patent Unex is mostly treated by pancreatic enzyme inhibitors such as a amined Publication No. 61197/1974) used as an antianxiety trypsin inhibitor. However, the therapeutic effects afforded drug; a 2-thienyltriazole compound (Japanese Patent Unex by them are not entirely satisfactory and a pharmaceutical amined Publication No. 69667/1974) used as an antianxiety agent exhibiting greater treatment effects has been desired. drug or an intermediate for pharmaceutical products; a Unlike other enzyme inhibitors, the CCK-A receptor antago 2-thienyltriazole compound (Japanese Patent Unexamined nist suppresses secretion of pancreatic enzyme itself and is Publication No. 58098/1975) which is an intermediate for a useful as a new agent for the treatment and prophylaxis of thienotriazolopyridine compound used as an antiinflamma pancreatitis. It is also effective for the treatment and pro tory drug, an antipyretic analgesic and the like; a phylaxis of gallbladder disorders, irritable bowel syndrome, 2-thienylimidazole compound (Japanese Patent Unexam 25 gastric ulcer, enterelicosis, emesis, pancreatic malignant ined Publication No. 893.69/1975) which has central muscle tumor, constipation and the like. relaxing activity, antianxiety activity and the like; a As a review on physiological activity of CCK and thera 2-thienyltriazole compound (Japanese Patent Examined peutic usefulness of CCK antagonists, there is known, for example, Annu. Rev. Pharmacol. Toxicol., Vol. 31, p. 469 Publication No. 45754/1982) used as a starting compound of 30 (1991). A compound having a CCK-A antagonistic activity, a pharmaceutical product such as an antianxiety drug; a such as proglumide, is reported in J. Med. Chem. Vol. 27, 2-thienyltriazole compound (Japanese Patent Unexamined p. 1597 (1984); a benzodiazepine compound, which is Publication No. 10568 1/1980) which is used as an anti typically devazepide 3(S)-1,3-dihydro-3-(2- anxiety drug; a 2-thienylimidazole compound (Japanese indolecarbonylamino)-1-methyl-5-phenyl-2H-1,4- Patent Unexamined Publication No. 105682/1980) which is 35 benzodiazepin-2-one). is reported in J. Med. Chem. Vol. 31, used as an antianxiety drug; a 2-thienylazole compound p. 2235 (1988); and a 2-acylamino-5-thiazole derivative is (Japanese Patent Unexamined Publication No. 294676/ reported in Japanese Patent Unexamined Publication No. 1989) having calmodulin antagonistic activity, coronary and 155871/1993. However, these compounds are not satisfac cerebral vasodilating activities and PAF antagonistic activ tory from the aspects of the level of activity in vitro or in ity; and the like. vivo, selectivity for CCK-A receptor, physicochemical prop In addition, Japanese Patent Unexamined Publication No. erties (e.g., solubility in water), bioavailability, safety and 102698/1974 discloses that a thienotriazolodiazepine com pound which may be substituted by the like, alkoxycarbonylaminoalkyl, alkylcarbonyloxyalkyl and the DISCLOSURE OF THE INVENTION like at the 9-position thereof can be used as a tranquilizer or 45 The present inventors conducted intensive studies with an antianxiety drug. Japanese Patent Unexamined Publica the aim of providing a useful compound which serves well tion Nos. 28.181/1990 and 223290/1991 disclose thienotria for the treatment and prophylaxis of various diseases caused Zolodiazepine compounds having cholecystokinin antago by peripheral CCK, by the action of selectively blocking the mistic activity, which have, at the 6-position thereof, an binding to CCK-A receptor, and found that certain thieny amide substituent (e.g., indole-2-carboxamide) or ureido 50 lazole compounds and thienotriazolodiazepine compounds substituent (e.g., (3-(3methylphenyl)ureidol, which sub can achieve the object, which resulted in the completion of stituent being considered to be essential for the expression of the present invention. Accordingly, the present invention cholecystokinin antagonistic activity. provides the following. The cholecystokinin (also referred to as CCK) is a neu (1) Thienylazole compounds of the formula ropeptide consisting of 33 amino acids, and CCK-8 which 55 consists of 8 amino acids at the C terminus also shows activity. The gastrin consists of 34 amino acids, and penta gastrin which consists of 5 amino acids at the C terminus also shows activity. The amino acid sequence of the penta gastrin is identical to that at the C terminus of CCK. There have been reported different subtypes of CCK receptors which are generally classified into CCK-A receptor distrib uted in peripheral tissues such as pancreas and gallbladder, and
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